Classifications

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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4245—Oxadiazoles
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  • A61K31/425—Thiazoles
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  • A61K31/425—Thiazoles
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  • A61K31/425—Thiazoles
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  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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  • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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  • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
  • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

• the present invention relates to a nitrogen-containing compound.
• this invention relates to a compound represented by formula (I) wherein all symbols are same meaning as defined hereinafter; and a salt thereof, a process for producing thereof and a pharmaceutical composition thereof as an active ingredient.
• Dipeptidyl peptidase IV is a member of the serine protease family, which cleaves a dipeptide, Xaa-Pro or Xaa-Ala, from a peptide having Pro or Ala as a second amino acid from N-terminal. It is widely expressed during a mammal organization, with the highest levels being in the kidney, liver, an intestinal tract epithelium, a placenta, and plasma. It is involved in metabolism of various bioactive peptides, especially strong in secretion of insulin. DPP-IV is remarkable for its activity to deactivate glucagon-like peptide-1 (GLP-1) which regulates postprandial blood glucose level.
• GLP-1 glucagon-like peptide-1
• GLP-1 non-insulin-dependent diabetes mellitus
• cleaved GLP-1 may weaken its effect. Therefore the best way to prolong GLP-1 activity is thought to prevent the degradation of GLP-1, namely inhibit DPP-IV, which is the most important enzyme to inactivate it.
• DPP-IV is expected useful in type 2 diabetes mellitus because it enhance GLP-1 activity, stimulate insulin release and improve glucose metabolism. It is also useful to anti-obesity agent of its appetite-reducing effect.
• DPP-IV has a relation to metabolism of neuropeptide Y, activation of immunocompetent cell, T-cell, adhesion of cancer cells to endothelia and penetration of a HIV to the lymphocyte. Therefore, it is thought that an inhibition of DPP-IV is useful for the medical treatment of an autoimmune disease, cancer transition, HIV infection, and the like
• DPP-IV highly expresses in dermal fibroblasts of patients with psoriasis, rheumatoid arthritis and lichen planus and its activity is high in patients with benign prostatic hyperplasia. It is also expected that an inhibition of DPP-IV is also useful for the medical treatment of dermatoses and benign prostatic hyperplasia.
• the compound of the formula (I) of the present invention is unknown as an inhibitor of DPP-IV.
• the present invention relates to
• a nitrogen-containing heterocyclic ring represented by ring A represents as following
• C1-8 carbon chain means C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-8 alkylidene, C3-8 alkenylidene and C3-8 alkynylidene.
• C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof.
• C2-8 alkenyl means ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and isomeric groups thereof.
• C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and isomeric groups thereof.
• C1-8 alkylidene means methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptylidene, octylidene and isomeric groups thereof.
• C3-8 alkenylidene means propenylidene, butenylidene, pentenylidene, hexenyllidene, heptenylidene, octenylidene and isomeric groups thereof.
• C3-8 alkynylidene means propynylidene, butynylidene, pentynylidene, hexynyllidene, heptynylidene, octynylidene and isomeric groups thereof.
• halogen atom means fluorine, chlorine, bromine and iodine.
• the "carbocyclic ring” represents "C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring”.
• C3-15 monocyclic, bicyclic or tricyclic carbocyclic ring represents a C3-15 monocyclic bicyclic or tricyclic carbocyclic aryl, or partially or completely saturated one thereof, a spiro-bound bicyclic carbocyclic ring and a crosslinked bicyclic carbocyclic ring.
• heterocyclic ring represents a "3-15 membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s)".
• the "3-15 membered monocyclic, bicyclic or tricyclic heterocyclic ring containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s)" represents 3-15 membered monocyclic, bicyclic or tricyclic heterocyclic aryl containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s), or partially or completely saturated one thereof,
• the "3-15 membered monocyclic, bicyclic or tricyclic heterocyclic aryl containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s)" represents, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepin, diazepin, furan, pyran, oxepine, thiophene, thiopyran, thiepin, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazin, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepin, indole, isoin
• the "3-15 membered monocyclic, bicyclic or tricyclic partially or completely saturated heterocyclic aryl containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s)” represents, for example, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroaze
• a ring which is formed by two R 1 taken together with abutting carbon atoms, that is a ring fused with ring A represents 3-10 membered monocyclic, bicyclic or tricyclic saturated or unsaturated carbocyclic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene, benzene, naphthalene, indan, and the like.
• a ring which is formed by two R 1 taken together with same carbons that is a spiro-carbocyclic ring (ring C) represents 3-15 membered monocyclic, bicyclic or tricyclic saturated or unsaturated carbocyclic ring, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclononene, cyclodecene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, cyclononadiene, cyclodecadiene, dihydronaphthalene, teterahydronaphthalene, indene
• a ring which is formed by two R 1 taken together with abutting carbon atoms, that is a ring fused with ring A represents 3-10 membered partially or completely saturated monocyclic or bicyclic heterocyclic ring containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s), for example, imidazole, thiazole, oxazole, pyrazole, imidazoline thiazolidine, oxazolidine, pyrolidine, dihydropyrrole, piperidine, dihydropyridine tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydropyran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, dihydrothiaine, tetrahydrothiaine, benzofuran, benzothiophene, indole, indoline, ind
• a ring which is formed by two R 1 taken together with same carbons that is a spiro-carbocyclic ring (ring C) represents 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring containing 1 to 5 hetero atom(s) selected from oxygen atom(s), nitrogen atom(s), and sulfur atom(s), for example, oxetane, azetidine, pyrrolidine, dihydropyrrole, piperidine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydropyran, dihydrofuran, tetrahydro thiophene, dihydrothiophene, dihydrothiain, tetrahydrothiain, tetrahydroquinoline, perhydroquinoline, dihydroindole, perhydroindole and the like.
• C1-8 carbon chain in “C1-8 carbon chain which may have substituents” represents same meaning as that of above described “C1-8 carbon chain”.
• substituteduents in "C1-8 carbon bond which may have substituents” represents, for example, 1-5 substituent(s) selected from hydroxyl, C1-8 alkoxy, mono(C1-8 alkyl)amino, di(C1-8 alkyl)amino, C2-8 acyl, C1-8 alkoxycarbonyl, benzyloxycarbonyl, carboxy, halogen, (C1-8 alkyl)sulfonylamino, C2-8 acylamino, phenyl, C3-8 cycloalkyl, and pyridyl.
• carbocyclic ring and “heterocyclic ring” in “carbocyclic ring or heterocyclic ring which may have substituents” represents same meaning as that of above described “carbocyclic ring” and “heterocyclic ring”.
• substituted in “carbocyclic ring or heterocyclic ring which may have substituents” represents, for example, 1-5 substituent(s) selected from C1-8 carbon chain, hydroxyl, C1-8 alkoxy, mono(C1-8 alkyl) amino, di(C1-8 alkyl)amino, C2-8 acyl, C1-8 alkoxycarbonyl, benzyloxycarbonyl, carboxy, halogen, (C1-8 alkyl)sulfonylamino, C2-8 acylamino, phenyl, C3-8 cycloalkyl, and pyridyl.
• 5-membered ring containing nitrogen represented by ring B includes, for example, pyrrolidine, oxazolidine, or thiazolidine whose sulfur atom may be oxidized.
• substituted in "5-membered hetrocyclic ring which may have substituents” represented by ring B includes same meaning as that of above described "substituent” in "carbocyclic ring or heterocyclic ring which may have substituents”.
• R 1 All groups represented by R 1 are preferable, more preferable R 1 is C1-8 alkyl which may have substituents, C2-8 alkenyl which may have substituents, C2-8 alkynyl which may have substituents, C1-8 alkylidene which may have substituents, carbocyclic ring which may have substituents, and heterocyclic ring which may have substituents.
• R 1 is C1-8 alkyl which may have substituents, carbocyclic ring which may have substituents, and heterocyclic ring which may have substituents.
• carbocyclic ring is C3-8 cycloalkane, benzene, adamantane.
• Preferable heterocyclic ring is pyridine, furan, thiophene, thiazole, benzodioxole.
• R 1 is benzene
• the substituent of benzene includes alkyl which may have substituents, hydroxyl, C1-8 alkoxy, acyl, phenoxy, carboxy, CONR 11 R 12 , OSO 2 R 13 , NR 11 SO 2 R 13 , halogen, cyano, carbocyclic ring which may have substituents, and heterocyclic ring which may have substituents,
• R 1 is benzene
• benzene has hydroxyl as a substituent, arbitrarily with C1-8 alkyl or C1-8 alkoxy, acyl, cyano, phenoxy even more.
• two R 1 as substituents of ring A, taken together may form spiro-cyclic ring C or fused ring D.
• k is an integer of 1 to 3, and more preferable k is an integer of 1 to 2.
• k is 0 or an integer of 1 to 3 and more preferable k is an integer of 1 to 2.
• Preferable Y is each of -CH 2 - and sulfur atom.
• R is each of hydrogen atom and cyano.
• Y is -CH 2 -
• preferable R is cyano.
• compound is the compound of formula (I-a) wherein all symbols represent same meanings as described above, formula (I-b) wherein all symbols represent same meanings as described above, formula (I-d) wherein k 0 represents 0 or an integer of 1 to 4; the other symbols represent same meaning as described above, formula (I-e) wherein all symbols represent same meanings as described above, formula (I-f) wherein all symbols represent same meanings as described above, formula (I-g) wherein all symbols represent same meanings as described above, formula (I-h) wherein all symbols represent same meanings as described above, formula (I-j) wherein all symbols represent same meanings as described above, formula (l-k) wherein all symbols represent same meanings as described above, formula (I-m) wherein all symbols represent same meanings as described above, formula (I-n) wherein all symbols represent same meanings as described above, and formula (I-p) wherein n represents 0 or an integer of 1 to 5, and
• alkyl, alkoxy, alkylthio, alkenyl, alkynyl, alkylene, alkylidene, alkenylidene, alkynylidene includes straight or branched one.
• isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, ⁇ -, ⁇ -configuration, enantiomer, diastereomer), optically active isomer (D-, L-, d-, I-configuration, (+)-, (-)-configuration), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, rotational isomer, mixtures thereof at voluntary ratio and racemic mixtures are also included in the present invention.
• a symbol means a bond to front side of the paper (i.e., ⁇ -configuration), a symbol means a bond to the opposite side of the paper (i.e., ⁇ -configuration), a symbol means a mixture of ⁇ - and ⁇ -configurations, and a symbol means either a bond to front side (i.e., ⁇ -confguration) or the opposite side (i.e., ⁇ -configuration) of the paper, but absolute configuration thereof is undecided.
• expressing double bonds means a mixture of E- and Z-isomer among geometrical isomer of double bond.
• compositions represented by formula (I) may be converted into the pharmaceutically acceptable salts by conventional means.
• pharmaceutically acceptable salts includes salts of alkali metals, salts of alkaline earth metals, salts of amines, acid addition salts, and the like.
• quaternary ammonium salts corresponding to thereof are included.
• salts nontoxic and water-soluble salts are preferred.
• Suitable salts include salts of alkali metals (potassium, sodium, and the like), salts of alkaline earth metals (calcium, magnesium, and the like), ammonium salts, pharmaceutically acceptable salts of organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxylmethyl)methylamine, lysine, arginine, N-methyl-D-glucamine, and the like) and preferable ones are salts of alkali metals thereof.
• Adequate acid addition salts includes salts of inorganic acid (hydrochloride, hydrobromide, sulfate, phosphate, nitrate, and the like), and salts of organic acid (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, ethane sulfonate, benzensuplhonate, toluenesulfonate, ise-thionate, glucuronic acid salt, gluconate, and the like).
• solvates nontoxic and water-soluble salts are preferred.
• the appropriate solvates include hydrates, solvate of ethanol etc, and preferably is hydrates.
• the compound represented by formula (I) may be produced by subjecting the compound represented by formula (II)
• X represents a protecting group of nitrogen atom and the other symbols represent same meaning as described above; to a deprotection reaction for a protective group of a nitrogen atom.
• the protecting group for nitrogen atom includes, for example, benzyloxycarbonyl, t-butoxy carbonyl, trifluoro acetyl, and 9-fluorenylmethoxycarbonyl.
• Each deprotection reaction of protecting group of nitrogen atom is well known, and it includes;
• the objective compounds of the present invention may be prepared easily by using these reactions.
• the compound represented by formula (I) also may be produced by subjecting the compound represented by formula (III)
• the amidation reaction is publicly known, and it includes;
• the compound represented by formula (II) may be produced by subjecting the compound represented by formula (IV) to an amidation reaction with formula (V)
• the compound represented by formula (V) in other words, the compounds represented by formulae (V-1), (V-2), (V-3), (V-4), (V-5), (V-6), ( ⁇ /-7), and (V-8) may be produced by the process shown in the following schemes 1-4.
• R 5a , R 5b , R 5c , R 5d represents same meaning as R 5 respectively
• R 6a , R 6b , R 6c , R 6d , R 6e , R 6f express represents same meaning as R 6 respectively ,with the proviso that at least one of R 6a , R 6b , R 6c , R 6d , R 6e , R 6f is hydrogen
• R 1A represents C1-8 alkyl optionally with substituents among R 1
• Boc represents t -butoxycarbonyl group
• Me represents methyl group
• tBu represents t -butyl group
• Et represents ethyl group
• Ts represents p-toluene sulfonyl group
• Tf represents trifluoromethane sulfonyl
• NaHMDS represents sodium hexamethyldisilazane.
• k1 when another R 1 exists, k1 represents 0 or an integer of 1 to 4, and when another R 1 doesn't exist, k1 represents 0 or an integer of 1 to 5.
• the compounds represented by formula (XXVI) may be produced by the method described in Tetrahedron Letters, 1998, 39, 5887-5890 or J.Org.Chem, 1995, 60 , 2925-2930.
• the compound represented by formula (V-11) which is a intermediate of the compound of formula (I), wherein may be produced by same method in scheme 1 or 3, using a corresponding compound that is the compound represented by formula (VI-a) or (XVIII-a) in stead of the compound represented by above formula (VI) or (XVIII).
• the compounds of the present invention also may be produced by subjecting the compounds produced by the above methods to a deprotection reaction of protecting group for amino group, hydroxyl group, mercapto group and/or carboxyl group if necessary.
• a protective group for carboxyl includes, for example, methyl, ethyl, allyl, t -butyl, trichloroethyl, benzyl (Bn), phenacyl, and the like.
• a protective group for hydroxyl includes, for example, methyl, trityl, methoxymethyl (MOM), 1-ethoxyethyl (EE), methoxyethoxymethyl (MEM), 2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES), t -butyldimethylsilyl (TBDMS), t -butyldiphenylsilyl (TBDPS), acetyl (Ac), pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like.
• MOM methoxymethyl
• EE 1-ethoxyethyl
• MEM methoxyethoxymethyl
• TMS trimethylsilyl
• TES triethylsilyl
• a protective group for amino includes, for example, benzyloxycarbonyl, t -butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-1-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl, 9-fluororenylmethoxycarbonyl, benzyl (Bn), p -methoxybenzyl, benzyloxymethyl (BOM), 2-(trimethylsilyl)ethoxymethyl (SEM), and the like.
• a protective group for mercapto includes, for example, benzyl, methoxybenzyl, methoxymethyl (MOM), 2-tetrahydropyranyl (THP), diphenylmethyl and acetyl (Ac).
• a protective group for carboxyl, hydroxyl, amino or thiol is not particularly limited in addition to the above-described groups as long as it can be deprotected easily and selectively.
• those described in Protective Groups in Organic Synthesis T. W. Greene, John Wiley & Sons Inc., 1999 may be used.
• the deprotection of the protective group for carboxyl, hydroxyl, amino or thiol is well known. For example, it is
• the deprotection may be carried out by the method described in Protective Groups in Organic Synthesis (T. W. Greene, John Wiley & Sons Inc., 1999),
• the objective compounds of the present invention may be prepared easily by using these deprotection reactions.
• the reaction product may be purified by a conventional purifying method such as distillation under ordinary or reduced pressure, high performance liquid chromatography, thin-layer chromatography or column chromatography using silica gel or magnesium silicate and recrystallization. Purification may be carried out for each reaction or after completion of some reactions.
• the toxicity of the compound of the present invention is very low, and it is believed that the compound is safe enough for pharmaceutical use.
• the compound of the present invention of formula (I) or salts thereof has an inhibitory activity of DPP IV, it is considered that it is useful as a preventive and/or therapeutic agent for type 2 diabetes mellitus, obesity, autoimmune disease, cancer metastasis, AIDS virus infection, dermatosis and benign prostatic hypertrophy.
• a combination agent obtained by combining the compound of formula (I) or a non-toxic salt thereof with other medicaments may be administered to accomplish the following purposes:
• a combination of the compound of formula (I) and other medicaments may be administered in the form of the formulations having these components incorporated in one preparation, or may be administered in separate preparations. In the case where these medicaments are administered in separate preparations, they may be administered simultaneously or at different times. In the latter case, the compound represented by formula (I) may be administered before the other medicaments. Alternatively, the other medicaments may be administered before the compound represented by formula (I). The method for the administration of these medicaments are the same or different.
• the diseases on which the preventive and/or therapeutic effect of the above described combination preparations works are not specifically limited but may be those for which the preventive and/or therapeutic effect of the compound represented by formula (I) is supplemented and/or enhanced.
• the other medicaments for supplementing and/or enhancing the action of the compound of formula (I) and for potentiation of therapeutic efficacy of diabetic complication remedy include, for example, hypoglycaemic agent of sulfonylurea, biguanide, ⁇ -glucosidase inhibitor, acute effect type insulin secretagogue, insulin sensitivity promoter, insulin formulation, PPAR agonist, ⁇ 3 adrenoceptor agonist, aldose reductase.
• sulfonylurea examples include acetohexamide, glibenclamide, gliclazide, glyclopyramide, chlorpropamide, tolazamide, tolbutamide, Glimepiride, and the like.
• biguanide examples include Buformin Hydrochloride, Metformin Hydrochloride and the like.
• ⁇ -glucosidase inhibitor examples include acarbose, voglibose and the like.
• fast-acting insulin secretagogue examples include nateglinide, repaglinide and the like.
• insulin sensitivity promoter examples include ONO-5816, YM-440, JTT-501, NN-2344 and the like.
• Examples of PPAR agonist include pioglitazone, troglitazone, rosiglitazone and the like.
• ⁇ 3 adrenoceptor agonist examples include AJ9677, troglitazone, L750355, CP331648 and the like.
• aldose reductase inhibitor examples include Epalrestat, Fidarestat, Zenarestat.
• the compounds represented by formula (I) and salts thereof may be combined with for example MTP (Microsomal Triglyceride Transfer Protein) inhibitor, HMG-CoA reductase inhibitor, squalene synthetase inhibitor, fibrate (fibrin acid derivative), ACAT (acyl-CoA:cholesterol O-acyl transferase) inhibitor, 5 - lipoxygenase inhibitor, cholesterol uptake inhibitor, bile acid uptake inhibitor, ileum Na+/bile acid cotransporter (ileal Na+/bile acid transporter ; IBAT) inhibitor, LDL receptor activator/expression promoter, lipase inhibitor, probucol formulation, nicotinic acid formulation, ohter antihypercholesterolemia therapeutic agent in order of complement or potentiation of lipid lowering action.
• MTP Mericrosomal Triglyceride Transfer Protein
• HMG-CoA reductase inhibitor HMG-CoA reductase inhibitor
• MTP inhibitor examples include BMS-201038, BMS-212122, BMS-200150, GW-328713, R-103757 and the like.
• HMG-CoA reductase inhibitor examples include atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, pitavastatin, Rosuvastatin and the like.
• ACAT inhibitor examples include F-12511, F-1394, CI-1011, melinamide and the like.
• squalene synthetase inhibitor examples include TAK-475 and the like.
• fibrate examples include gemfibrozil, clofibrate, clofibrate aluminum, clinofibrate, simfibrate, bezafibrate, fenofibrate and the like.
• ACAT inhibitor examples include CI-1011, FCE27677, RP73163 and the like.
• cholesterol uptake inhibitor examples include SCH48461 and the like.
• bile acid uptake inhibitor examples include colestyramine, colesevelam and the like.
• LDL receptor activator/enhanced expression agent examples include MD-700, LY295427 and the like.
• lipase inhibitor examples include orlistat and the like.
• the ratio by mass of the compounds of formula (I) to other drugs is not particularly limited.
• Two or more of other drugs optionally selected can be used in combination.
• drugs to be used for complementing and/or enhancing the preventive and/or therapeutic effects of the compounds of formula (I) involve not only those which have been found out hitherto based on the above-described mechanism but also those which will found out in future.
• the single administration dose to an adult usually ranges from 1 ng to 100 mg and the administration is made once to several times per day in the case of oral administration.
• the single administration dose ranges from 0.1 ng to 10 mg and the administration is made once to several times per day in the case of parenteral administration.
• intravenous administration is continuously made for 1 hour to 24 hours per day.
• the administration dose varies depending on various factors as described above.
• an administration dose smaller than the lower limit as defined above is enough in some cases, while an administration dose exceeding the upper limit is needed in other cases.
• Examples of the solid preparations for internal use include tablets, pills, capsules, dusts, granules and the like.
• the capsules include hard capsules and soft capsules.
• Such a solid preparation for internal use is prepared by a formulation method commonly employed by using one or more active substances either as such or as a mixture with an excipient (lactose, mannitol, glucose, microcrystalline cellulose, starch, and the like), a binder (hydroxypropylcellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, and the like) a disintegrating agent (calcium cellulose glycolate, and the like), a lubricant (magnesium stearate, and the like), a stabilizer, and a dissolution aid (glutamic acid, aspartic acid, and the like).
• an excipient lactose, mannitol, glucose, microcrystalline cellulose, starch, and the like
• a binder hydroxypropylcellulose, polyvinylpyrrolidone, magnesium metasilicate aluminate, and the like
• a disintegrating agent calcium cellulose glycolate, and the like
• a lubricant magnesium
• a coating agent sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, and the like. It may be coated with two or more layers. Moreover, capsules made of an absorbable material such as gelatin are involved in the scope thereof.
• the liquid preparations for internal use involve pharmaceutically acceptable solutions, suspensions, emulsions, syrups, elixirs and the like.
• a liquid preparation is prepared by dissolving, suspending or emulsifying one or more active substances in a diluent commonly employed (purified water, ethanol, a mixture thereof, and the like).
• the liquid preparation may further contain a moistening agent, a suspending agent, an emulsifier, a sweetener, a flavor, a perfume, a preservative, a buffer and the like.
• Injections for use in parenteral administration include sterile aqueous, suspension, emulsion and solid forms used by dissolving or suspending in solvent before use. Injection is used by dissolving, suspending, or emulsifying one or more active substances in solvent.
• solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol and combinations thereof.
• this injection may contain stabilizer, solubilizer (glutamic acid, aspartic acid, polysorbate 80 (registered trademark), and the like), suspending agent, emulsifying agent, analgesic agent, buffering agent, preservative agent, and the like. They may also be manufactured in the form of sterile solid forms, for example, freeze-dried products, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
• the dosage forms of the parenteral administration preparations for external use involve ointments, gels, creams, fomentations, patches, liniments, atomized agents, inhalations, sprays, aerosols, nasal drops and the like.
• Such a preparation contains one or more active substances and is prepared by a publicly known method or in accordance with a formulation commonly employed.
• Ointments are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by levigating or melting one or more active substances in a base.
• the ointment base is selected from among publicly known ones or those commonly employed. For example, use may be made of one base or a mixture of two or more thereof selected from higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid esters, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, and the like), waxes (beeswax, whale wax, ceresin, and the like), surfactants (polyoxyethylene alkyl ether phosphoric acid esters, and the like), higher alcohols (cetanol, stearyl alcohol, cetostaryl alcohol, and the like), silicone oils (dimethylpolysiloxane, and the
• Gels are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by melting one or more active substances in a base.
• the gel base is selected from among publicly known ones or those commonly employed. For example, use may be made of one base or a mixture of two or more thereof selected from among lower alcohols (ethanol, isopropyl alcohol, and the like), gelling agents (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, and the like), neutralizing agents (triethanolamine, diisopropanolamine, and the like), surfactants (polyethylene glycol monostearate, and the like), gums, water, absorption promoters and skin irritation inhibitors.
• the gels may further contain a preservative, an antioxidant, a flavor, and the like.
• Creams are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by melting or emulsifying one or more active substances in a base.
• the cream base is selected from among publicly known ones or those commonly employed. For example, use may be made of one base or a mixture of two or more thereof selected from among higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, and the like), higher alcohols (2-hexyldecanol, cetanol, and the like), emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, and the like), water, absorption promoters and skin irritation inhibitors.
• the creams may further contain a preservative, an antioxidant, a flavor, and the like.
• Fomentations are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by melting one or more active substances in a base, kneading and then applying and spreading the kneaded matter on a substrate.
• the fomentation base is selected from among publicly known ones or those commonly employed.
• use may be made of one base or a mixture of two or more thereof selected from among thickeners (polyacrylic acid, polyvinylpyrrolidone, acacia, starch, gelatin, methylcellulose, and the like), moistening agents (urea, glycerol, propylene glycol, and the like), fillers (kaolin, zinc oxide, talc, calcium, magnesium, and the like), water, dissolution aids, tackifiers and skin irritation inhibitors.
• the fomentations may further contain a preservative, an antioxidant, a flavor, and the like.
• Patches are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by melting one or more active substances in a base and then applying and spreading on a substrate.
• the patch base is selected from among publicly known ones or those commonly employed. For example, use may be made of one base or a mixture of two or more thereof selected from among polymer bases, fats and oils, higher fatty acids, tackifiers and skin irritation inhibitors.
• the patches may further contain a preservative, an antioxidant, a flavor, and the like.
• Liniments are prepared in accordance with a publicly known formulation or a formulation commonly employed. For example, they are prepared by dissolving, suspending or emulsifying one or more active substances in one or more media selected from among water, alcohols (ethanol, polyethylene glycol, and the like), higher fatty acids, glycerol, soap, emulsifiers, suspending agents and the like.
• the liniments may further contain a preservative, an antioxidant, a flavor, and the like
• Atomized agents, inhalations, sprays and nasal drop may contain, in addition to a diluent commonly employed, a stabilizer such as sodium hydrogen sulfite, a buffer for imparting isotonicity, for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid.
• a stabilizer such as sodium hydrogen sulfite
• a buffer for imparting isotonicity for example, an isotonic agent such as sodium chloride, sodium citrate or citric acid.
• a nasal drop When a nasal drop is administered, it is usually administered by spraying (atomizing) solution or powder containing drug into nasal cavity with a dedicated nasal drip apparatus or atomizer quantitatively.
• Eye drops for parenteral administration may be in the form of liquid, suspension, emulsion, liquid dissolved in a solvent in use or ointment.
• eye drops are prepared by any known method.
• one or more active substances are dissolved, suspended or emulsified in a solvent.
• a solvent for eye drops there may be used sterilized purified water, physiological saline and other aqueous solvents or nonaqueous solvents for injection (vegetable oils, and the like), singly or in combination thereof.
• the eye drops may contain ones selected from an isotonic agent (sodium chloride, concentrated glycerin, and the like), a buffering agent (sodium phosphate, sodium acetate, and the like), a surfactant (Polysolvate 80 (trade name), Polyoxyl stearate 40, polyoxyethylene-hydrogenated castor oil, and the like), a stabilizer (sodium citrate, sodium edetate, and the like), a preservative (benzalconium chloride, paraben, and the like), and the like.
• the eye drops are sterilized at the final step or prepared by an aseptic process.
• an aseptic solid agent such as freeze-dried product which has previously been prepared may be rendered aseptic or dissolved in aseptic distilled water for injection or other solvent before use.
• the dosage of inhalations for parenreral administration include aerosol, powders for inhalation or liquids for inhalation.
• the liquids for inhalation may be dissolved or suspended in water or the other appropriate solvent as needed.
• Such inhalations are prepared in a known method.
• a liquid for inhalation is prepared by selecting proper additives from an antiseptic (benzalkonium chloride, p -aminobenzonic acid and the like), a coloring agent, a buffering agent (sodium phosphate, sodium acetate and the like), an isotonizing agent (sodium chloride, concentrated glycerin and the like), thickening agent (carboxyvinylpolymer and the like), or an accelerator of absorption, and the like, if necessary.
• a powder for inhalation is prepared by selecting proper additives from a lubricant agent (such as stearin acid and the salt thereof), a binding agent, (starch, dextrin and the like), a diluting agent (lactose, cellulose and the like), a coloring agent, an antiseptic (benzalkonium chloride, p-aminobenzonic acid and the like), an accelerator of absorption, and the like, if necessary.
• a lubricant agent such as stearin acid and the salt thereof
• a binding agent starch, dextrin and the like
• a diluting agent lactose, cellulose and the like
• a coloring agent such as benzalkonium chloride, p-aminobenzonic acid and the like
• an accelerator of absorption and the like, if necessary.
• spray atomizer, nebulizer
• powder for inhalation inhalation administration apparatus for powder agents is usually used.
• compositions for parenteral administration include suppositories for intrarectal administration and pessaries for vaginal administration which comprise one or more of the active substance(s) and may be prepared by methods known per se.
• the solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations or TLC.
• the solvents in the parentheses in NMR show the solvents for measurement.
• dimethyl sulfoxide represents dimethyl sulfoxide
• DMF represents N,N-dimethylformamide
• THF represents tetrahydrofuran.
• the aqueous layer was acidified by adding 1 N hydrochloric acid and was extracted with ethyl acetate. The organic layer was concentrated. The residue was dissolved into 1N aqueous solution of sodium hydride. The mixture was washed with diethyl ether. The aqueous layer was acidified by adding 1 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated. The residue was dissolved in ethyl acetate and dicyclohexylamine was added to the mixture.
• the precipitate was obtained by filtration, washed with ethyl acetate and dried. Ethyl acetate and 1N hydrochloric acid were added to the obtained solid. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried and concentrated to give the title compound (1.20 g).
• the compound prepared in Reference Example 30 (3.21 g) was dissolved in methanol (30 ml), and 10% palladium carbon (50% water content; 850 mg) was added to the mixture. The mixture was stirred for 90 minutes under an atmosphere of hydrogen gas. The reaction mixture was filtrated. The filtrate was concentrated to give the title compound (2.55 g). The title compound was racemate mixture whose relative configuration was cis.
• Example 1 (1) - Example 1 (4)
• the compound of the present invention was obtained, using the compound prepared in Reference Example 3, by the same procedure as Reference Example 1 ⁇ Example 1 (Trifluoroacetic acid was used instead of hydrogen chloride-ethyl acetate which was used in Example 1.).
• the compound of the present invention was obtained, using a corresponding compound, by the same procedure as Reference Example 2 ⁇ Example 3 ⁇ Example 2 (in some case, hydrogen chloride-ethyl acetate solution, hydrogen chloride-dioxane solution may be used instead of trifluoroacetic acid).
• the compound of the present invention was obtained, using the compound prepared in Reference Example 9, by the same procedure as Reference Example 1 ⁇ Example 1.
• the compound of the present invention was obtained, using the compound of Reference Example 11, by the same procedure as Reference Example 1 (if necessary converting into corresponding salt by known methods.).
• the compound of the present invention was obtained, using the compound of Reference Example 17, by the same procedure as Reference Example 1 ⁇ Example 1 and then being separated by column chromatography on silica gel.
• the compound of the present invention was obtained, using the compound of Reference Example 22, by the same procedure as Reference Example 1 ⁇ Example 1.
• the compound of the present invention was obtained, by the same procedure as Reference Example 23 ⁇ Reference Example 24 ⁇ Reference Example 25 ⁇ Reference Example 26 ⁇ Example 8.
• the compound of the present invention was obtained, using the compound of Reference Example 28, by the same procedure as Example 1.
• the compound of the present invention was obtained, using the compound of Reference Example 32, by the same procedure as Reference Example 11 ⁇ Reference Example 1 ⁇ Example 1.
• Example 16 was prepared using the compound in Reference Example 31 as a material.
• Example 14 The title compound was obtained, using the compound prepared in Example 15, by the same procedure as Reference Example 3 ⁇ Reference Example 1 (glycine benzyl ester was used.) ⁇ catalytic reduction (it was carried out, by the same procedure as Reference Example 5, using hydroxylation palladium in ethyl acetate.) ⁇ Example 14.
• Example 16 (2) The compound prepared in Example 16 (2) was protected by Boc, by the same procedure as Reference Example 3.
• the obtained compound 250 mg was dissolved into THF (2 ml). Pyridine (0.18ml) and trifluoroacetic anhydride (0.12ml) were added to the reaction solution at 0 °C and the mixture was stirred for 2 hours at 0 °C. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate, washed with 0.1N hydrochloric acid, water and a saturated solution of sodium chloride successively, dried and concentrated. The residue was washed with ether-ethyl acetate (5/1) to give the title compound protected by Boc (156 mg).
• Example 19 The compound prepared in Example 19 (29) (IA-255) was carried out, by the same procedure as Reference Example 3 to give Boc protected compound.
• the Boc protected compound (230 mg) was dissolved into methylethylketone (3 ml). Potassium carbonate (414 mg) and a bromoacetic acid benzyl (0.29 ml) were added to the solution and the mixture was refluxed for 1 hour.
• the reaction mixture was diluted with ethyl acetate, washed with water and a saturated solution of sodium chloride successively, dried with sulfuric anhydride magnesium and concentrated.
• Example 15 The compound prepared in Example 15 was operated, by the same procedure as Reference Example 3. p -toluenesulfonic acid monohydrate (119 mg) was added to a solution of the obtained compound (200 mg) in ethanol (2 ml) and the mixture was refluxed for 4 hours. The reaction mixture was concentrate. The residue was washed with ethyl acetate to give the title compound (184 mg).

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